Exploring Endogenous Heart Repair and Regeneration

For the millions of people who suffer from heart attacks every year, the aftereffects are literally scarring. When the heart muscle dies from lack of blood, it is replaced by scar tissue, since the heart has very little regenerative capacity. While better medical care and timely management of heart attacks have decreased the number of early deaths, survivors face an increased risk of chronic heart failure as they develop even more scarring. This grim prospect is what stem cell scientists, like Dr. Deepak Srivastava, Director of Cardiovascular Disease and the Stem Cell Center at the Gladstone Institutes in San Francisco, are hoping to change.

Stem Cells in Focus Webcast

An Introduction to Endogenous Heart Repair

Deepak Srivastava, MD, Gladstone Institutes, USA

Learn more about the research and its potential, and pose your questions directly to Dr. Srivastava, during a live public webcast, Thursday, February 20 at 2 pm ET (USA).

They plan to fix the heart from the inside – a strategy called endogenous (self) repair – by stimulating resident heart cells to generate new cardiomyocytes, the specialized heart muscle cells that keep our hearts beating.

But why does the heart need help regenerating in the first place? Well, scientists used to think that our heart muscle cells were with us for life. It turns out, by the time we reach the age of 50, approximately half of all the cells in the heart aren’t the ones we were born with. While this is welcome proof that the heart can regenerate enough to maintain itself, the slow rate of turnover – about 0.5 to 1% per year – is far too low to repair damaged heart muscle.

The source for new muscle cells for heart turnover is still a black box. There might be a pool of heart stem cells that slowly churn out new muscle cells. Or that might be the role of stem cells circulating in the blood that set up shop in the heart. Or there may be unknown factors that trigger existing heart muscle cells to multiply. These theories are all being explored.

One of the reasons that scientists have turned to endogenous repair for answers, is that clinical trials transplanting adult stem cells from a variety of sources have not panned out as hoped. While the safety profiles have been encouraging, the level of heart recovery has been minimal at best. Scientists are not yet sure why, but they are exploring the possibilities around increasing stem cell survival, expanding the numbers of patient-derived stem cells, and finding agents that can attract stem cells to damaged heart tissue for future trials.

But is there any evidence for endogenous repair of the heart? This area of research is in early days, but the answer seems to be yes: there are internal switches that can kick start heart muscle cells in newborn mice; there are heart cells in newly born mammals that look like they might be able to make new heart muscle; and there are experiments showing how non-muscle cells in the heart can be coopted to become heart muscle cells.

An example of a heart muscle cell that was created from a reprogrammed fibroblast. A protein specific to heart muscles is visualized by the green fluorescence.

The last example brings us back to Dr. Srivastava’s approach. His team is the first to show that fibroblasts, structural support cells found throughout the body, can be directly converted, or reprogrammed, into heart muscle cells. Figuring out the conversion process was no simple task. First, they identified a pool of 14 different factors known to be used by nature to make a heart in an embryo. Then they painstakingly whittled the number down to three essential factors. Finally, they introduced the factors into fibroblasts by way of a virus delivery system and found that the three factors were enough to convert the fibroblasts into cells that looked very much like heart muscle. In mice with heart damage similar to a heart attack in humans, the three factors not only created new muscle, but also improved the pumping of the heart. This reprogramming process is novel because it triggers the conversion of one specialized cell directly into another specialized cell, without first being forced to become a stem cell.

Having shown that it’s possible to directly reprogram mouse fibroblasts (in a dish and in adult hearts) and also human heart fibroblasts in a dish, Dr. Srivastava’s group is testing the recipe in pigs, whose heart size and physiology is closer to our own.

So what are some of the pros and cons of direct reprogramming? A big plus is that this represents a new way to fix damaged heart tissue - and since the heart is over 50% fibroblasts, there are ample cells to reprogram. The major issue is safety: there is always the chance of causing tumors when using virus delivery systems. Many researchers are trying to find ways around this; one possibility is identifying small drug-like molecules that could replace the reprogramming-factor / virus delivery combination. Dr. Srivastava’s main concern is the risk of irregular heartbeats that could happen if the newly made heart muscle cells, located in patchy, scarred areas of the heart, start beating out of sync because they are not able to connect with existing heart muscle cells.

In the best of all worlds, Dr. Srivastava estimates the direct reprogramming approach might reach clinical trials within five years. The first trials would primarily assess safety but would also begin to probe what really happens inside a human heart, perhaps through testing in patients scheduled for heart transplantation, allowing scientists to study their old hearts post-transplant. While such trials are well into the future, the possibility of repairing the heart via direct reprogramming does offer some much needed hope for all those who face the prospect of heart failure.